Naturally occurring somatostatins (SSTs), which are also known as somatotropin release-inhibiting factors (SRIFs), have diverse biological effects in many cells and organs throughout the body. They are produced by normal endocrine, gastrointestinal, immune and neuronal cells, as well as by certain tumors (Patel, Y. C., Frontiers in Neuroendocrinology, 20(3): 157-198 (1999); Froidevaux, et al., Biopolymers, 66(3): 161-83 (2002)). The effects of somatostatins are broadly inhibitory on the secretion of hormones, as well as on the proliferation and survival of cells. They inhibit both endocrine secretion (e.g., growth hormone, insulin, glucagon, gastrin, cholecystokinin, vasoactive intestinal peptide, and secretin) and exocrine secretion (e.g., gastric acid, intestinal fluid and pancreatic enzymes) (Patel. Y. C., (1999) op. cit.). Somatostatins also inhibit proliferation of both normal and tumor cells (Bousquet, et al., Chemotherapy, 47(2): 30-39 (2001)).
These biological effects of somatostatins, all inhibitory in nature, are elicited through a series of G protein-coupled receptors, of which five different subtypes have been characterized (SSTR1-5) (Reubi, et al., Cancer Res, 47: 551-558 (1987); Reisine, et al., Endocrine Review, 16: 427-442 (1995); Patel, Y. C., (1999) op. cit.). SSTR1-5 have similar affinities for the endogenous somatostatin ligands but have differing distribution in various tissues.
Somatostatin analogs were initially developed for the control of hormonal syndromes associated with neuroendocrine tumors (NETs). In recent years, accumulating data has supported their role as antiproliferative agents, capable of stabilizing tumor growth in patients with metastatic neuroendocrine malignancies, including carcinoid and pancreatic endocrine tumors (Strosberg, et al., World J Gastroenterol, 26(24): 2963-2970 (2010)).
Examples of somatostatin analogs are disclosed in, e.g., PCT publication Nos. WO 02/10215; WO 2007/144492; WO 2010/037930; WO 99/22735; and WO 03/014158.
Dopamine is a catecholamine neurotransmitter that has been implicated in the pathogenesis of both Parkinson's disease and schizophrenia (Graybiel, et al., Adv. Neurol., 53: 17-29 (1990); Goldstein, et al., FASEB Journal, 6: 2413-2421 (1992); Olanow, et al., Annu. Rev. Neurosci., 22, 123-144 (1999)). Dopamine and related molecules have been shown to inhibit the growth of several types of malignant tumors in mice, and this activity has been variously attributed to inhibition of tumor-cell proliferation, stimulation of tumor immunity or effects on melanin metabolism in malignant melanomas. (Wick, M. M., J. Invest. Dermatol., 71: 163-164 (1978); Wick, M. M., J. Natl. Cancer Inst., 63: 1465-1467 (1979); Wick, M. M., Cancer Treat Rep., 63: 991-997 (1979); Basu, et al., Endocrine, 12: 237-241 (2000); Basu, et al., J. Neuroimmunol., 102: 113-124 (2000)).
It has been shown that dopamine receptor subtype DRD2 and somatostatin receptor subtype SSTR2, as well as other somatostatin receptor subtypes and members of the dopamine and opiate receptor families, interact physically through hetero-oligomerization to create a novel receptor with enhanced functional activity (Rocheville, et al., Science, 288(5463): 154-157 (2000); Baragli, et al., Hetero-oligomerization of dopamine (D2R) and SST receptors (SSTR2) in CHO—K1 cells and cortical cultured neurons, Proc. 85th Endo. Soc. Meeting, Philadelphia, Pa., USA (2003) (Abstract P2-669); Pfeiffer, et al., J. Biol. Chem., 277: 19762-19772 (2002)).
A combination of basic research observations concerning the interaction of somatostatin and dopamine receptors and clinical reports of enhanced efficacy of combined somatostatin and dopamine analog treatment in suppressing growth hormone hypersecretion led to the concept of creating chimeric molecules combining structural features of both compound classes. Examples of somatostatin-dopamine chimeric molecules are disclosed in U.S. patent application publication No. US 2004/0209798 and PCT publication Nos. WO 2004/091490, WO 2002/100888, and WO 2009/139855.
Exemplary somatostatin-dopamine chimeric molecules are taught in the art to retain the ability to interact with receptors of both families and display greatly enhanced potency and efficacy, as compared with that of individual SST or DA receptor agonists. In vitro studies with pituitary adenoma cells from acromegalic patients have demonstrated that the chimeric molecules have exceptional activity with regard to suppression of growth hormone and prolactin secretion by pituitary adenoma cells from acromegalic patients (Saveanu, et al., J Clin Endocrinol Metab, 87(12): 5545-5552 (2002); Jaquet, et al., European Journal of Endocrinology, 153: 135-141 (2005)). Similarly, potent suppression of ACTH secretion from Cushing's-causing corticotroph tumors, and suppression of nonfunctioning pituitary adenoma proliferation has been observed (Florio, et al., Endocrine-Related Cancer, 15: 583-596 (2008)). The somatostatin-dopamine chimeric compounds are also quite potent and efficacious in suppressing both growth hormone and IGF1 in vivo when tested in nonhuman primates, with no effect on either insulin secretion or glycemic control (Culler, et al., The somatostatin-dopamine chimeric molecule, BIM-23A760, does not induce the insulin/glycemic effects observed with individual somatostatin or dopamine agonists in cynomolgus monkeys (Macaca fascicularis), 12th Meeting of the European Neuroendocrine Association, Athens, Greece (2006)).
Initial clinical studies examining acute, subcutaneous administration of select somatostatin-dopamine chimeric compounds revealed both prolonged circulating half-life and extended duration of biological effect (Culler, M., Horm Metab Res, 43(12): 854-857 (2011)). With chronic administration, however, select somatostatin-dopamine chimeric compounds were found to produce a metabolite with dopaminergic activity that gradually accumulates and interferes with the activity of the parent compound (Culler, M., (2011) op. cit.).
Clearly, needs remain for additional somatostatin-dopamine chimeric analogs having improved activity for use in, inter alia, the inhibition, prevention, and/or treatment of neuroendocrine tumors and/or diseases.